ONE STEP PROCESS FOR THE PREPARATION OF PHENYL ETHYL AMINE DERIVATIVES

Abstract

The present invention relates to a novel process for the preparation of phenyl ethyl amine derivatives by reacting a phenyl ethyl hydroxy compound with hydrogen cyanide followed by in situ hydrolysis.

Claims

1. A process for the preparation of a compound of formula (I) ##STR00015## wherein R1 is independently selected from halogen, nitro, cyano, formyl, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, C1-C5 alkoxy, C3-C5 alkenyloxy, C3-C5 alkynyloxy and C1-C5 alkylthio, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and alkylthio is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, cyano and C1-C3 alkylthio; n is 0, 1, 2, 3, 4 or 5; R2 is selected from C.sub.1-C.sub.5 alkyl, C.sub.3-C.sub.5 cycloalkyl and C.sub.2-C.sub.5 alkenyl, wherein C.sub.1-C.sub.5 alkyl, C.sub.3-C.sub.5 cycloalkyl and C.sub.2-C.sub.5 alkenyl are unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, cyano, C.sub.1-C.sub.3 alkyl and C.sub.1-C.sub.3 alkoxy; said process comprising reacting a compound of formula (II) ##STR00016## wherein R1, n and R2 are as defined for a compound of formula (I), with (a) hydrogen cyanide under acidic conditions, followed by (b) subsequent addition of water into the reaction mixture to obtain a compound of formula (I).

2. The process according to claim 1, wherein R1 is independently selected from fluoro, bromo, chloro, cyano, methyl and methoxy wherein the methyl and methoxy are unsubstituted or substituted with 1 to 3 substituents independently selected from fluoro and chloro; n is 0, 1 or 2; R2 is selected from C.sub.1-C.sub.5 alkyl and C.sub.3-C.sub.5 cycloalkyl, wherein the C.sub.1-C.sub.5 alkyl and C.sub.3-C.sub.5 cycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from halogen.

3. The process according to claim 1, wherein R1 is independently selected from fluoro, bromo and chloro; n is 0 or 1; R2 is selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, —CH.sub.2CF.sub.3, —CH.sub.2—C(CH.sub.3).sub.3, —CH.sub.2—C(CH.sub.3).sub.2F and —CH.sub.2—C(CH.sub.3)F.sub.2.

4. The process according to claim 1, wherein n is 0 or 1 and when n is 1, then R1 is fluoro, bromo or chloro and attached at the ortho (1-position) or meta (2-position) position of the phenyl ring; R2 is selected from methyl, ethyl, n-propyl, isopropyl and isobutyl.

5. The process according to claim 1, wherein the reaction mixture is charged with 1-50 mole equivalents of water relative to the compound of formula (II).

6. The process according to claim 1, wherein the reaction (a) of the compound of formula (II) with hydrogen cyanide under acidic conditions is carried out at a temperature between 50° C. and 100° C.

7. The process according to claim 1, wherein the reaction (a) is carried out by the addition of a cyanide salt to a suitable solvent, and then the addition of a strong acid and a compound of formula (II).

8. The process according to claim 7, wherein the cyanide salt is potassium cyanide and the strong acid is sulfuric acid.

9. The process according to claim 8, wherein the reaction (b) is carried out at a temperature between 75° C. and 100° C.

Description

EXPERIMENTAL

Examples

[0025] The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon.

[0026] Compound Synthesis and Characterisation The following abbreviations are used throughout this section: s=singlet; bs=broad singlet; d=doublet; dd=double doublet; dt=double triplet; bd=broad doublet; t=triplet; td=triplet doublet; bt=broad triplet; tt=triple triplet; q=quartet; m=multiplet; Me=methyl; Et=ethyl; Pr=propyl; Bu=butyl; DME=1,2-dimethoxyethane; THF=tetrahydrofuran.

Example 1: 2-Methyl-1-phenyl-propan-2-amine

[0027] ##STR00005##

[0028] A suspension of potassium cyanide (0.135 g, 1.997 mmol) in acetic acid (0.22 mL, 3.861 mmol) was prepared and cooled with an ice/water bath to 0-10° C. In the meanwhile a mixture of sulfuric acid (0.255 mL, 4.527 mmol) and acetic acid (0.22 mL, 3.861 mmol) was prepared. A strong exothermic effect was observed. Then the acidic solution was added dropwise to the suspension over 5 min. The reaction mixture changed into a milky suspension. 2-methyl-1-phenyl-propan-2-ol (0.2 g, 1.331 mmol) was added drop wise to the suspension over 5 min and the reaction mixture was heated to 80° C. After 3 h stirring at this temperature water (0.240 mL, 13.314 mmol) was added in one portion and it was stirred over night at 80° C.

[0029] The cooled down reaction mixture was poured slowly on cold sat. Na2CO3-solution. A gas formation could be observed during the addition as expected. It was extracted 3× with tert-butyl methyl ether.

[0030] The organic layers were combined, washed once with brine and dried over Na.sub.2SO4. It was filtered and evaporated to obtain 2-methyl-1-phenyl-propan-2-amine with a purity of 93.0% and 89.2% chemical yield.

[0031] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.15 (s, 6H) 1.49 (br s, 2H) 2.69 (s, 2H) 7.19-7.36 (m, 5H)

Example 2: 1-(2-Fluorophenyl)-2-methyl-propan-2-amine

[0032] ##STR00006##

[0033] Procedure as above for Example 1. 1-(2-Fluorophenyl)-2-methyl-propan-2-amine was obtained with a purity of 72% and 61.6% chemical yield.

[0034] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.17 (d, 6H) 1.64 (br s, 2H) 2.75 (d, 2H) 7.00-7.18 (m, 2H) 7.19-7.26 (m, 2H)

Example 3: 1-(2-Chlorophenyl)-2-methyl-propan-2-amine

[0035] ##STR00007##

[0036] Procedure as above for Example 1. 1-(2-Chlorophenyl)-2-methyl-propan-2-amine was obtained with a purity of 86% and 87.6% chemical yield.

[0037] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.20 (s, 6H) 1.61 (br s, 2H) 2.91 (s, 2H) 7.16-7.33 (m, 3H) 7.35-7.45 (m, 1H)

Example 4: 1-(3-Fluorophenyl)-2-methyl-propan-2-amine

[0038] ##STR00008##

[0039] Procedure as above for Example 1. 1-(3-Fluorophenyl)-2-methyl-propan-2-amine was obtained with a purity of 39% and 24.3% chemical yield.

[0040] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.26 (s, 6H) 2.78-2.87 (m, 2H) 3.71-3.99 (br s, 2H) 6.90-7.05 (m, 3H) 7.23-7.33 (m, 1H)

Example 5: 2-Methyl-1-(o-tolyl)propan-2-amine

[0041] ##STR00009##

[0042] Procedure as above for Example 1. 2-Methyl-1-(o-tolyl) propan-2-amine was obtained with a purity of 64.4% and 58.9% chemical yield.

[0043] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.18 (s, 6H) 1.66 (br s, 2H) 2.39 (s, 3H) 2.77 (s, 2H) 7.13-7.22 (m, 4H)

Example 6: 1-(2-bromophenyl)-2-methyl-propan-2-amine

[0044] ##STR00010##

[0045] Procedure as above for Example 1. 1-(2-Bromophenyl)-2-methyl-propan-2-amine was obtained with a purity of 72.9% and 73.2% chemical yield.

[0046] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.22 (s, 6H) 1.73 (br s, 2H) 2.95 (s, 2H) 7.08-7.15 (m, 1H) 7.23-7.35 (m, 2H) 7.59 (d, 1H)

Example 7: 2-Methyl-1-phenyl-butan-2-amine

[0047] ##STR00011##

[0048] Procedure as above for Example 1. 2-Methyl-1-phenyl-butan-2-amine was obtained with a purity of 83% and 78.1% chemical yield.

[0049] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 0.96-1.02 (m, 3H) 1.05 (s, 3H) 1.34-1.51 (m, 4H) 2.68 (s, 2H) 7.17-7.36 (m, 5H)

Example 8: 2-Methyl-1-phenyl-pentan-2-amine

[0050] ##STR00012##

[0051] Procedure as above for Example 1. 2-Methyl-1-phenyl-pentan-2-amine was obtained with a purity of 86% and 31.7% chemical yield.

[0052] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 0.96 (t, 3H) 1.12 (s, 3H) 1.36-1.53 (m, 4H) 2.71 (br s, 2H) 2.74 (s, 2H) 7.19-7.35 (m, 5H)

Example 9: 2,4-Dimethyl-1-phenyl-pentan-2-amine

[0053] ##STR00013##

[0054] Procedure as above for Example 1. 2,4-Dimethyl-1-phenyl-pentan-2-amine was obtained with a purity of 93% and 85.0% chemical yield.

[0055] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.01 (dd, 6H) 1.08 (s, 3H) 1.2 (brs, 2H) 1.37 ((qd)m, 2H) 1.83-1.93 (m, 1H) 2.65-2.72 (m, 2H) 7.19-7.35 (m, 5H)

Example 10: 1-(3-Fluorophenyl)-2,4-dimethyl-pentan-2-amine

[0056] ##STR00014##

[0057] Procedure as above for Example 1. 1-(3-Fluorophenyl)-2,4-dimethyl-pentan-2-amine was obtained with a purity of 57% and 43.9% chemical yield.

[0058] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.01 (dd, 6H) 1.09 (s, 3H) 1.28-1.44 (m, 4H) 1.84-1.90 (m, 1H) 2.68 (s, 2H) 6.92-7.00 (m, 3H) 7.27 (m, 1H)